WO2021213380A1 - Forme solide de nicotinamide substitué par pyrazine, sa préparation et son utilisation - Google Patents

Forme solide de nicotinamide substitué par pyrazine, sa préparation et son utilisation Download PDF

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WO2021213380A1
WO2021213380A1 PCT/CN2021/088378 CN2021088378W WO2021213380A1 WO 2021213380 A1 WO2021213380 A1 WO 2021213380A1 CN 2021088378 W CN2021088378 W CN 2021088378W WO 2021213380 A1 WO2021213380 A1 WO 2021213380A1
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compound
formula
crystalline form
diffraction pattern
ray powder
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PCT/CN2021/088378
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Chinese (zh)
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王义汉
赵九洋
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深圳市塔吉瑞生物医药有限公司
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Priority to EP21792938.9A priority Critical patent/EP4122928A4/fr
Priority to CN202311156373.3A priority patent/CN117304171A/zh
Priority to CN202180029222.4A priority patent/CN115413277B/zh
Priority to US17/920,001 priority patent/US20230322717A1/en
Priority to JP2022563455A priority patent/JP2023522110A/ja
Publication of WO2021213380A1 publication Critical patent/WO2021213380A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the technical field of medicine, and particularly relates to (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine- 2-yl)nicotinamide (compound A or compound of formula (A)) or the crystalline form of its pharmaceutically acceptable salt, its preparation method, and the preparation of said compound for treatment with Bcr-Abl kinase and its Mutant-mediated diseases, such as chronic myelogenous leukemia, in medicine.
  • the present invention also relates to a method for preparing Compound A, and a preparation containing Compound A.
  • Compound A is an Abl1 allosteric inhibitor targeting the myristoyl binding site, which can be used to treat diseases mediated by Bcr-Abl kinase and its mutants, such as chronic myeloid leukemia.
  • International Patent Publication No. WO 2018/133827 A1 first disclosed the compound, but did not disclose the crystalline form of compound A.
  • the applicant for WO 2018/133827 A1 is Shenzhen Tarirui Biomedical Co., Ltd., and its corresponding Chinese application CN 201880000986.9 was announced on August 27, 2019 under the authorization announcement number CN 108602800 B.
  • WO 2018/133827 A1 has corresponding US application US 16/479,299, European application EP 18741306.7 and Japanese application JP 2019-560440. The content of each of the foregoing applications is incorporated herein by reference in its entirety.
  • the invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine-2 -Yl)nicotinamide (Compound A) in various crystalline forms of the free base.
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine 2-yl)nicotinamide Form I (Compound A Form I).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine (Azin-2-yl)nicotinamide Form II (Compound A Form II).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine (Azin-2-yl)nicotinamide Form III (Compound A Form III).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine
  • the crystalline form IV of azin-2-yl)nicotinamide (Compound A crystalline form IV).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine
  • the crystalline form V of azin-2-yl)nicotinamide (Compound A crystalline form V).
  • the invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine
  • the crystalline form VI of azin-2-yl)nicotinamide (Compound A crystalline form VI).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine (Azin-2-yl)nicotinamide Form VII (Compound A Form VII).
  • the invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine (Azin-2-yl)nicotinamide Form VIII (Compound A Form VIII).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine
  • the crystalline form IX of azin-2-yl)nicotinamide (Compound A crystalline form IX).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine
  • the crystalline form X of azin-2-yl)nicotinamide (Compound A crystalline form X).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyridine (Azin-2-yl)nicotinamide, Form XI (Compound A, Form XI).
  • the present invention provides multiple crystalline forms of the salt of Compound A.
  • the invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide hydrochloride and its hydrochloride crystalline form I (Compound A hydrochloride crystalline form I).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide benzenesulfonate and its benzenesulfonate crystal form I (Compound A benzenesulfonate crystal form I).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide p-toluenesulfonate and its p-toluenesulfonate crystalline form I (Compound A p-toluenesulfonate crystalline form I).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide p-toluenesulfonate and its p-toluenesulfonate crystal form II (Compound A p-toluenesulfonate crystal form II).
  • the present invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide methanesulfonate and its methanesulfonate crystal form I (Compound A methanesulfonate crystal form I).
  • the invention provides (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazine -2-yl)nicotinamide hydrobromide and its hydrobromide crystalline form I (Compound A hydrobromide crystalline form I).
  • the present invention provides a method for preparing compound A crystal form VI, which comprises converting compound A crystal form VII into compound A crystal form VI.
  • the present invention provides a method of preparing a compound of formula (A):
  • X is halogen; preferably I or Br; more preferably I;
  • the present invention provides a method of preparing a compound of formula (A):
  • X is halogen; preferably I or Br; more preferably I;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a pharmaceutically active ingredient: the crystalline form of the free base of Compound A or the crystalline form of a pharmaceutically acceptable salt thereof, (ii) a diluent, (iii) ) Disintegrant, (iv) glidant, and (v) lubricant.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a compound of formula (A), (ii) a diluent, (iii) a disintegrant, (iv) a glidant, and (v) Lubricants, wherein the weight percentage of the glidant is 1-5%, preferably 2-4%, preferably about 3% of the total weight of the pharmaceutical composition.
  • the present invention provides the use of the above crystal form in the preparation of a medicament for the treatment and/or prevention of diseases caused by Bcr-Abl.
  • the present invention provides the above-mentioned crystal form for use in the treatment and/or prevention of diseases caused by Bcr-Abl.
  • the present invention provides a method for treating and/or preventing diseases caused by Bcr-Abl in a subject, comprising administering the above-mentioned crystal form to the patient.
  • the diseases caused by the above-mentioned Bcr-Abl include solid tumors, sarcomas, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, Rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases; or the disease caused by Bcr-Abl1 is metastatic invasive cancer, viral infection or CNS disorder.
  • Figure 3 XRPD comparison diagrams of compound A crystal form I before and after the DVS test.
  • Figure 30 XRPD images of compound A crystal form III, crystal form VI and crystal form VII before and after grinding.
  • Figure 33 XRPD comparison chart of Compound A Hydrochloride Form I before and after the DVS test.
  • Figure 36 XRPD comparison diagrams of compound A besylate crystalline form I before and after the DVS test.
  • Figure 39 XRPD comparison diagram of compound A p-toluenesulfonate crystalline form I before and after the DVS test.
  • Figure 40 XRPD pattern of compound A p-toluenesulfonate salt form II.
  • Figure 43 XRPD comparison diagram of Compound A mesylate salt form I before and after DVS test.
  • Figure 46 XRPD comparison diagram of compound A hydrobromide salt crystalline form I before and after the DVS test.
  • Figure 48 XRPD pattern of the crystal form change of compound A crystalline form I when dissolved in SGF.
  • Figure 49 XRPD pattern of the crystal form change of compound A crystalline form I when dissolved in FaSSIF.
  • Figure 50 XRPD pattern of the crystal form change of compound A crystal form I when dissolved in FeSSIF.
  • Figure 51 XRPD pattern of the crystal form change of compound A p-toluenesulfonate salt form I when dissolved in SGF.
  • Figure 52 XRPD pattern of the crystal form change of compound A p-toluenesulfonate salt form I when dissolved in FaSSIF.
  • Figure 53 XRPD pattern of the crystal form change of compound A p-toluenesulfonate form I when dissolved in FeSSIF.
  • Figure 54 A crystal structure diagram of Compound A.
  • Figure 55 Compound A crystal form VI stability study XRPD pattern.
  • the term “substantially” refers to taking into account the typical variability of a particular method and the standard error of the measured value.
  • the term “substantially” refers to the typical variability in consideration of peak positions and intensity.
  • the peak position (2 ⁇ ) will show some variability, usually up to ⁇ 0.2°.
  • the relative peak intensity will show variability between devices as well as variability due to crystallinity, preferred orientation, sample surface tested, and other factors known to those skilled in the art.
  • the NMR spectra (ppm) of 1 H, 13 C, and 19 F show variability, usually as high as ⁇ 0.2 ppm.
  • crystalline and crystalline form refer to a solid composed of molecules with a regular and repeating arrangement.
  • the crystalline form can be different in terms of thermodynamic stability, physical parameters, X-ray structure and preparation process.
  • amorphous refers to a solid composed of a disordered arrangement of molecules.
  • solvate refers to a crystal form having a chemical amount or a non-chemical amount of solvent (such as water, methanol, ethyl acetate, etc., or a mixture thereof) through non-covalent intermolecular bonding in the crystal lattice .
  • solvent such as water, methanol, ethyl acetate, etc., or a mixture thereof
  • hydrate refers to a solvate in which the solvent is water.
  • anhydrous refers to a crystalline form that contains less than about 1% (w/w) adsorbed moisture as determined by a standard method such as Karl Fisher analysis.
  • the present invention relates to multiple crystalline forms of Compound A, such as “Compound A Crystal Form I”, “Compound A Crystal Form II”, “Compound A Crystal Form III”, “Compound A Crystal Form IV”, “Compound A Crystal Form V” ", “Compound A crystal form VI”, “Compound A crystal form VII”, “Compound A crystal form VIII”, “Compound A crystal form IX”, “Compound A crystal form X” and “Compound A crystal form XI”.
  • the crystalline form of these compounds may be in the form of solvates, hydrates, or non-solvates.
  • the present invention provides compound A crystal form I, which is an ethanol solvate, wherein the molar ratio of ethanol to free base is 1:2.
  • the X-ray powder diffraction pattern of the crystal form I obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 18.3 ⁇ 0.2 and 24.4 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 9.6 ⁇ 0.2, 19.3 ⁇ 0.2, 21.8 ⁇ 0.2, 22.5 ⁇ 0.2, and 24.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 10.7 ⁇ 0.2, 12.2 ⁇ 0.2, 16.2 ⁇ 0.2, 22.8 ⁇ 0.2, 23.4 ⁇ 0.2, and 27.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.1. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 1.
  • the crystalline form I has a melting endothermic peak at 173 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form I has a weight loss of about 5.1% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A crystal form II, which is an acetonitrile solvate, wherein the molar ratio of acetonitrile to free base is 1:5.
  • the X-ray powder diffraction pattern of the crystal form II obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 11.0 ⁇ 0.2, 11.6 ⁇ 0.2, 13.0 ⁇ 0.2, 17.1 ⁇ 0.2, 19.6 ⁇ 0.2, 19.8 ⁇ 0.2 and 22.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 5.8 ⁇ 0.2, 6.4 ⁇ 0.2, 10.8 ⁇ 0.2, 14.9 ⁇ 0.2, 15.3 ⁇ 0.2, 16.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.6 ⁇ 0.2, 23.3 ⁇ 0.2, 25.1 ⁇ 0.2 and 26.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.2. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 4.
  • the crystalline form II has a melting endothermic peak at 115 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form II has a weight loss of about 1.9% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A crystal form III, which is a hydrate, wherein the molar ratio of water to free base is 1:1.
  • the X-ray powder diffraction pattern of Form III obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 12.4 ⁇ 0.2, 14.2 ⁇ 0.2, 20.0 ⁇ 0.2, and 21.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 7.0 ⁇ 0.2, 9.3 ⁇ 0.2, 13.9 ⁇ 0.2, and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 15.3 ⁇ 0.2, 20.6 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, 28.3 ⁇ 0.2, and 28.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.3. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 5.
  • the crystalline form III has a melting endothermic peak at 173 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form III has a weight loss of about 3.5% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A, crystalline form IV, which is a methanol solvate, wherein the molar ratio of methanol to free base is 1:2.
  • the X-ray powder diffraction pattern of the crystal form IV obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 9.7 ⁇ 0.2, 22.5 ⁇ 0.2, and 24.4 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 6.2 ⁇ 0.2, 12.9 ⁇ 0.2, 18.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.2 ⁇ 0.2, and 24.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 6.4 ⁇ 0.2, 10.8 ⁇ 0.2, 12.3 ⁇ 0.2, 16.0 ⁇ 0.2, 19.2 ⁇ 0.2, 21.1 ⁇ 0.2 and 27.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.4. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 6.
  • the crystalline form IV has endothermic peaks at 176 ⁇ 2°C and 251 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form IV has a weight loss of about 3.7% before 200°C in the thermogravimetric analysis.
  • the crystal form IV has the following unit cell parameters:
  • the present invention provides compound A, crystalline form V, which is an isobutanol solvate, wherein the molar ratio of isobutanol to free base is 1:6.
  • the X-ray powder diffraction pattern of the crystal form V obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 9.4 ⁇ 0.2, 18.1 ⁇ 0.2, 18.9 ⁇ 0.2, 21.3 ⁇ 0.2 and 23.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 24.3 ⁇ 0.2 and 26.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 9.9 ⁇ 0.2, 11.8 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 17.6 ⁇ 0.2, 18.4 ⁇ 0.2, 19.1 ⁇ 0.2, 19.8 ⁇ 0.2, 21.8 ⁇ 0.2 and 23.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.5. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 7.
  • the crystalline form V has a melting endothermic peak at 173 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form V has a weight loss of about 6.5% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A crystal form VI, which is an anhydrate.
  • the X-ray powder diffraction pattern of the crystal form VI obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 11.9 ⁇ 0.2, 20.5 ⁇ 0.2, 23.1 ⁇ 0.2, 23.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 9.7 ⁇ 0.2, 16.1 ⁇ 0.2, 19.3 ⁇ 0.2, and 21.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 5.9 ⁇ 0.2, 11.0 ⁇ 0.2, 12.8 ⁇ 0.2, 14.7 ⁇ 0.2, 16.6 ⁇ 0.2, 17.8 ⁇ 0.2, 18.2 ⁇ 0.2, 18.6 ⁇ 0.2, 20.1 ⁇ 0.2, 22.0 ⁇ 0.2, 22.6 ⁇ 0.2, 26.2 ⁇ 0.2 and 29.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.6. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 8.
  • the crystalline form VI has a melting endothermic peak at 175 ⁇ 2°C in the differential scanning calorimetry analysis.
  • Form VI has a DSC pattern substantially as shown in FIG. 20.
  • the crystalline form VI has substantially no weight loss before 200°C in the thermogravimetric analysis. In another embodiment, Form VI has a TGA pattern substantially as shown in FIG. 21.
  • the crystal form VI has an absorption peak at the following cm -1 in the infrared absorption spectrum: 853 ⁇ 2, 1020 ⁇ 2, 1062 ⁇ 2, 1210 ⁇ 2, 1408 ⁇ 2, 1466 ⁇ 2, 1491 ⁇ 2, 1599 ⁇ 2, 1661 ⁇ 2, 3293 ⁇ 2.
  • the crystal form VI has an infrared absorption spectrum substantially as shown in FIG. 23.
  • the crystalline form VI has absorption peaks at the following nm in the UV spectrum: 201 ⁇ 2, 263 ⁇ 2, and 306 ⁇ 2.
  • Form VI has a UV spectrum substantially as shown in FIG. 19.
  • the present invention provides compound A crystal form VII, which is a hydrate, wherein the molar ratio of water to free base is 1:1.
  • the X-ray powder diffraction pattern of crystalline form VII obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 11.7 ⁇ 0.2, 16.9 ⁇ 0.2, 18.3 ⁇ 0.2, 20.9 ⁇ 0.2, 21.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.8 ⁇ 0.2 and 27.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 13.4 ⁇ 0.2, 16.0 ⁇ 0.2, 20.7 ⁇ 0.2, and 22.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 13.2 ⁇ 0.2, 19.6 ⁇ 0.2, 21.3 ⁇ 0.2, 25.7 ⁇ 0.2, and 30.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.7. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 24.
  • the crystalline form VII has a melting endothermic peak at 174 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form VII has a weight loss of about 3.4% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A crystal form VIII, which is an ethanol solvate, wherein the molar ratio of ethanol to free base is 2:5.
  • the X-ray powder diffraction pattern of the crystal form VIII obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 9.6 ⁇ 0.2, 12.7 ⁇ 0.2, 18.3 ⁇ 0.2, 19.1 ⁇ 0.2, 22.8 ⁇ 0.2 and 24.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 10.7 ⁇ 0.2, 12.1 ⁇ 0.2, 19.4 ⁇ 0.2, 21.8 ⁇ 0.2, 22.5 ⁇ 0.2, 24.7 ⁇ 0.2 and 27.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.8. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 25.
  • the present invention provides compound A crystal form IX, which is a solvate of ethanol, isopropanol and tetrahydrofuran, wherein the molar ratio of ethanol to free base is 1:2, and the molar ratio of isopropanol to free base The ratio is 1:3, and the molar ratio of tetrahydrofuran to free base is 0.06:1.
  • the X-ray powder diffraction pattern of crystalline form IX obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 9.6 ⁇ 0.2, 18.2 ⁇ 0.2, and 22.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 6.1 ⁇ 0.2, 12.1 ⁇ 0.2, 12.4 ⁇ 0.2, 19.0 ⁇ 0.2, 19.3 ⁇ 0.2, 21.5 ⁇ 0.2, 24.4 ⁇ 0.2 and 24.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 10.5 ⁇ 0.2, 16.1 ⁇ 0.2, 20.6 ⁇ 0.2, 21.2 ⁇ 0.2, 23.6 ⁇ 0.2, 26.9 ⁇ 0.2, 27.7 ⁇ 0.2 and 28.4 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.9. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 26.
  • the crystalline form IX has a melting endothermic peak at 174 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form IX has a weight loss of about 5.8% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A, crystalline form X, which is a tetrahydrofuran solvate, wherein the molar ratio of tetrahydrofuran to free base is 1:12.
  • the X-ray powder diffraction pattern of the crystalline form X obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 7.0 ⁇ 0.2, 9.3 ⁇ 0.2, 12.3 ⁇ 0.2, 14.2 ⁇ 0.2, 16.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2 and 23.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 15.4 ⁇ 0.2, 19.2 ⁇ 0.2, 19.5 ⁇ 0.2, 22.2 ⁇ 0.2, 23.4 ⁇ 0.2, 24.8 ⁇ 0.2, 25.8 ⁇ 0.2, 26.2 ⁇ 0.2, 26.7 ⁇ 0.2, 28.8 ⁇ 0.2 and 29.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2 ⁇ value in Table 3.10. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 27.
  • the crystalline form X has a melting endothermic peak at 173 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form X has a weight loss of about 3.6% before 200°C in the thermogravimetric analysis.
  • the present invention provides compound A, crystalline form XI, which is an acetonitrile solvate, wherein the molar ratio of acetonitrile to free base is 2:5.
  • the X-ray powder diffraction pattern of crystalline form XI obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 9.7 ⁇ 0.2, 17.9 ⁇ 0.2, 19.5 ⁇ 0.2, 24.2 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 7.6 ⁇ 0.2, 12.7 ⁇ 0.2, 13.2 ⁇ 0.2, 18.7 ⁇ 0.2, 18.9 ⁇ 0.2, 22.4 ⁇ 0.2 and 25.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 14.6 ⁇ 0.2, 16.7 ⁇ 0.2, 20.2 ⁇ 0.2, 20.7 ⁇ 0.2, 21.0 ⁇ 0.2, 21.3 ⁇ 0.2, 26.0 ⁇ 0.2 and 29.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.11. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 28.
  • the crystalline form XI has a melting endothermic peak at 174 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the crystalline form XI has a weight loss of about 3.9% before 200°C in the thermogravimetric analysis.
  • the present invention relates to various salts of Compound A, such as hydrochloride, benzenesulfonate, p-toluenesulfonate, methanesulfonate and hydrobromide.
  • the present invention also relates to the crystalline crystal forms of various salts of Compound A, such as “Compound A Hydrochloride Crystal Form I”, “Compound A Besylate Crystal Form I”, and “Compound A p-toluenesulfonate Crystal Form I” ", “Compound A p-toluenesulfonate crystalline form II”, “Compound A methanesulfonate crystalline form I” and “Compound A hydrobromide crystalline form I”.
  • the present invention provides compound A hydrochloride crystalline form I.
  • the hydrochloride salt form I is an anhydrate.
  • the X-ray powder diffraction pattern of the hydrochloride crystal form I obtained by using CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 6.5 ⁇ 0.2, 13.8 ⁇ 0.2, 18.7 ⁇ 0.2 And 23.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 11.3 ⁇ 0.2, 15.7 ⁇ 0.2, 16.4 ⁇ 0.2, 21.9 ⁇ 0.2, 22.7 ⁇ 0.2, 24.2 ⁇ 0.2 and 28.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 16.8 ⁇ 0.2, 19.7 ⁇ 0.2, 20.8 ⁇ 0.2, 21.3 ⁇ 0.2, 25.2 ⁇ 0.2, and 35.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.1. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 31.
  • the hydrochloride salt form I has a melting endothermic peak at 229 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the hydrochloride salt form I has a weight loss of about 0.7% at 175°C in a thermogravimetric analysis.
  • the present invention provides compound A besylate salt crystalline form I.
  • the besylate salt form I is an anhydrate.
  • the X-ray powder diffraction pattern of besylate salt crystal form I obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 7.6 ⁇ 0.2, 10.2 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 16.4 ⁇ 0.2, 19.1 ⁇ 0.2, 19.9 ⁇ 0.2, 21.3 ⁇ 0.2, 21.9 ⁇ 0.2, and 23.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 25.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern includes one or more peaks at the 2[Theta] value in Table 3.2. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 34.
  • the besylate salt form I has a melting endothermic peak at 253 ⁇ 2° C. in the differential scanning calorimetry analysis.
  • the benzenesulfonate salt form I has a weight loss of about 0.5% at 200°C in a thermogravimetric analysis.
  • the present invention provides compound A p-toluenesulfonate crystalline form I.
  • the p-toluenesulfonate salt form I is an anhydrate.
  • the X-ray powder diffraction pattern of p-toluenesulfonate crystal form I obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 7.4 ⁇ 0.2, 10.2 ⁇ 0.2, 21.3 ⁇ 0.2 and 21.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes a characteristic peak represented by the following °2 ⁇ : 27.9 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 14.9 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 23.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.3. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 37.
  • the p-toluenesulfonate salt form I has a melting endothermic peak at 236 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the p-toluenesulfonate salt form I has a weight loss of about 0.1% at 200°C in a thermogravimetric analysis.
  • the present invention provides compound A p-toluenesulfonate crystalline form II.
  • the p-toluenesulfonate salt form II is an anhydrate.
  • the X-ray powder diffraction pattern of p-toluenesulfonate crystal form II obtained by using CuK ⁇ radiation includes at least characteristic peaks located in the following °2 ⁇ : 6.4 ⁇ 0.2, 7.4 ⁇ 0.2, 10.2 ⁇ 0.2, 16.3 ⁇ 0.2, 21.3 ⁇ 0.2 and 21.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.4. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 40.
  • the p-toluenesulfonate salt form II has a melting endothermic peak at 234 ⁇ 2°C in the differential scanning calorimetry analysis.
  • the p-toluenesulfonate salt form II has a weight loss of about 0.2% at 200°C in a thermogravimetric analysis.
  • the present invention provides compound A mesylate salt crystalline form I.
  • the mesylate salt form I is an anhydrate.
  • the X-ray powder diffraction pattern of the mesylate salt crystal form I obtained by CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 19.7 ⁇ 0.2 and 23.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 4.7 ⁇ 0.2, 16.4 ⁇ 0.2, 18.7 ⁇ 0.2, 19.2 ⁇ 0.2, 22.3 ⁇ 0.2, and 22.7 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 20.1 ⁇ 0.2, 28.1 ⁇ 0.2, and 37.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.5. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 41.
  • the mesylate salt form I has a melting endothermic peak at 206 ⁇ 2°C in differential scanning calorimetry analysis.
  • the mesylate salt form I has a weight loss of about 0.7% at 200°C in a thermogravimetric analysis.
  • the present invention provides compound A hydrobromide salt crystalline form I.
  • the hydrobromide salt crystalline form I is an anhydrate.
  • the X-ray powder diffraction pattern of the hydrobromide salt crystal form I obtained by CuK ⁇ radiation includes at least the characteristic peaks represented by the following °2 ⁇ : 6.4 ⁇ 0.2, 13.5 ⁇ 0.2, 20.6 ⁇ 0.2, 21.1 ⁇ 0.2, 23.8 ⁇ 0.2, 24.0 ⁇ 0.2 and 26.1 ⁇ 0.2.
  • the X-ray powder diffraction pattern further includes characteristic peaks represented by the following °2 ⁇ : 13.0 ⁇ 0.2 and 28.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern has the following characteristic peaks:
  • the X-ray powder diffraction pattern comprises one or more peaks at the 2[Theta] value in Table 3.6. In another embodiment, the X-ray powder diffraction pattern is substantially as shown in FIG. 44.
  • the hydrobromide salt crystal form I has a melting endothermic peak at 251 ⁇ 2°C in differential scanning calorimetry analysis.
  • the hydrobromide salt crystal form I has a weight loss of about 0.6% at 200°C in a thermogravimetric analysis.
  • the present invention relates to a method for preparing kilogram-level high-purity compound A and its crystal form VI, see scheme 1.
  • Step 1 Substituting compound D with 3-(R)-fluoropyrrolidine hydrochloride in the presence of a base, preferably an inorganic base.
  • Step 2 In the presence of a specific palladium catalyst and base acetate, compound C is reacted with dual pinacol borate to form intermediate compound B or its boric acid hydrolysate or a mixture of the two, and then in the presence of palladium catalyst and base Next, it reacts with 2-halopyrazine to produce compound A, and preferably recrystallizes to obtain compound A crystal form VII.
  • Step 3 The compound A crystal form VII is converted into the compound A crystal form VI.
  • Step 1 is to react compound D with 3-(R)-fluoropyrrolidine hydrochloride to form compound C in the presence of a base.
  • the reaction is carried out in an aprotic solvent in the presence of a base.
  • the base is an inorganic base, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate; Preferably sodium carbonate, potassium carbonate or cesium carbonate; preferably sodium carbonate.
  • the aprotic solvent is selected from the group consisting of DCM, DCE, ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, n-heptane, petroleum ether, acetone, acetonitrile, toluene, methyl acetate Butyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, DMF, DMA or DMSO; preferably acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, DMF or DMSO; preferably DMSO.
  • reaction is performed at 50°C to the reflux temperature of the solvent, preferably 50-90°C, more preferably 70 ⁇ 10°C for at least 1 hour, preferably at least 20 hours.
  • Step 2 is to make compound C react with double pinacol borate in the presence of palladium catalyst Pd(dppf)Cl 2 and double pinacol borate to produce intermediate compound B and its boric acid hydrolysate or a mixture of the two (Step 2 -1), and then react with 2-halopyrazine in the presence of a palladium catalyst and a base to form compound A (step 2-2).
  • step 2-1 the reaction is as follows:
  • the reaction includes combining the compound of formula (C) with dual pinacol boric acid in the presence of a palladium catalyst Pd(dppf)Cl 2 and acetic acid base.
  • Ester reaction wherein the solvent is selected from DMSO, DCM, DCE, ethyl acetate, methyl acetate, isopropyl acetate, acetone, acetonitrile, methyl tert-butyl ether, ethylene glycol monomethyl ether, ethylene glycol bis Methyl ether, DMF or DMA; preferably DMSO, 2-methyltetrahydrofuran, ethylene glycol monomethyl ether or DMF; preferably DMSO.
  • step 2-1 wherein the base acetate is selected from potassium acetate, sodium acetate or cesium acetate; preferably potassium acetate.
  • step 2-1 wherein the amount of base acetate is 2-5 times that of compound C; preferably 2.5 times.
  • step 2-1 wherein the amount of the dual pinacol borate is 3-6 times that of compound C; preferably 3 times.
  • step 2-1 wherein the amount of the catalyst used is 0.01-0.1 times of compound C, preferably 0.05 times.
  • step 2-1 wherein the reaction is carried out at 60°C to solvent reflux temperature, preferably 60-100°C, more preferably 80 ⁇ 10°C; preferably, the reaction time is at least 1 hour, preferably At least 2 hours.
  • step 2-2 the reaction is as follows:
  • X is halogen; preferably I or Br; more preferably I.
  • the reaction includes combining the compound of formula (B), its boric acid hydrolysate, or a mixture of the two with 2-halopyrazine in the presence of a palladium catalyst and a base. React in DMSO or DMF.
  • step 2-2 wherein DMSO or DMF contains water in a volume ratio of 0.01-0.5:1; preferably, the volume ratio of water is 0.05-0.2:1, preferably 0.067:1, 0.1: 1 or 0.2:1.
  • step 2-2 wherein the base is selected from sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, quaternary ammonium salt, NaF, KF, CsF, sodium bicarbonate, bicarbonate Potassium, disodium hydrogen phosphate or dipotassium hydrogen phosphate.
  • step 2-2 wherein the quaternary ammonium salt is selected from the group consisting of tetrabutyl amine fluoride, tetrabutyl amine bromide, tetraethyl amine fluoride, tetraethyl amine bromide, The organic quaternary ammonium salt of methyl ammonium fluoride, tetramethyl ammonium bromide or tetramethyl ammonium chloride; preferably tetrabutyl ammonium fluoride.
  • step 2-2 wherein the base is selected from sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, tetrabutylamine fluoride, NaF, KF and CsF.
  • the palladium catalyst is selected from 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, palladium acetate, tetrakis(triphenylphosphine) ) Palladium, tris(dibenzylideneacetone)dipalladium, palladium dichloride or bis(triphenylphosphine)palladium dichloride; preferably 1,1'-bis(diphenylphosphino)ferrocene dichloride Palladium, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium or bis(triphenylphosphine)palladium dichloride; preferably 1,1'-bis(diphenylphosphino)di Ferrocene palladium dichloride.
  • step 2-2 wherein the molar ratio of 2-halopyrazine to compound B or its boric acid hydrolysate or a mixture of the two is 0.8-1.5:1; preferably 1.2:1.
  • step 2-2 wherein the amount of the base is 1-3.5 times of compound B or its boric acid hydrolysate or a mixture of the two; preferably 1.2-2.7 times; preferably 1.2, 1.5, 1.8 , 2.0, 2.1, 2.2, 2.4 or 2.7 times.
  • step 2-2 wherein the amount of the palladium catalyst is 0.005-0.1 times of compound B or its boric acid hydrolysate or a mixture of the two; preferably 0.01-0.05 times; preferably 0.01, 0.02, 0.03, 0.04 or 0.05 times.
  • step 2-2 wherein the reaction is at room temperature to solvent reflux temperature, preferably 30-80°C, more preferably 30 ⁇ 5°C, 50 ⁇ 5°C, 65 ⁇ 5°C or 80 ⁇ 5 Reaction at °C; preferably, the reaction time is at least 1 hour, preferably at least 3 hours.
  • step 2-2 the reaction is as follows:
  • X is halogen; preferably I or Br; more preferably I.
  • the reaction includes combining the compound of formula (B), its boric acid hydrolysate, or a mixture of the two with 2-halogenated in the presence of a palladium catalyst and a quaternary ammonium salt. Pyrazine reaction.
  • step 2-2 wherein the quaternary ammonium salt is selected from the group consisting of tetrabutyl amine fluoride, tetrabutyl amine bromide, tetraethyl amine fluoride, tetraethyl amine bromide, The organic quaternary ammonium salt of methyl ammonium fluoride, tetramethyl ammonium bromide or tetramethyl ammonium chloride; preferably tetrabutyl ammonium fluoride.
  • the palladium catalyst is selected from 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, palladium acetate, tetrakis(triphenylphosphine) ) Palladium, tris(dibenzylideneacetone)dipalladium, palladium dichloride or bis(triphenylphosphine)palladium dichloride; preferably 1,1'-bis(diphenylphosphino)ferrocene dichloride Palladium, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium or bis(triphenylphosphine)palladium dichloride; preferably 1,1'-bis(diphenylphosphino)di Ferrocene palladium dichloride.
  • step 2-2 wherein the molar ratio of 2-halopyrazine to compound B or its boric acid hydrolysate or a mixture of the two is 0.8-1.5:1; preferably 1.2:1.
  • step 2-2 wherein the amount of the base is 1-3.5 times that of compound B or its boric acid hydrolysate or a mixture of the two; preferably 1.2-2.7 times; preferably 1.2, 1.5, 1.8 , 2.0, 2.1, 2.2, 2.4 or 2.7 times.
  • step 2-2 wherein the amount of the palladium catalyst is 0.005-0.1 times of compound B or its boric acid hydrolysate or a mixture of the two; preferably 0.01-0.05 times; preferably 0.01, 0.02, 0.03, 0.04 or 0.05 times.
  • step 2-2 wherein the reaction is selected from the group consisting of DCM, DCE, ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, n-heptane, petroleum ether, acetone, acetonitrile , Toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, water, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, DMF, DMA, DMSO solvents or their mixtures
  • the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol monomethyl ether, isopropanol, water, toluene, DMF, DMSO or mixtures thereof; preferably tetrahydrofuran, DMF, isopropanol, water , Toluene or
  • step 2-2 wherein the reaction is at room temperature to solvent reflux temperature, preferably 30-80°C, more preferably 30 ⁇ 5°C, 50 ⁇ 5°C, 65 ⁇ 5°C or 80 ⁇ 5 Reaction at °C; preferably, the reaction time is at least 1 hour, preferably at least 3 hours.
  • Step 3 is the conversion of compound A crystal form VII to compound A crystal form VI.
  • step 3 includes the step of dissolving compound A crystal form VII in an acetone solution, concentrating at normal pressure, adding n-heptane in two steps, and then distilling at normal pressure.
  • the temperature is 75 ⁇ 5°C. This conversion of crystal form yields substantially pure compound A crystal form VI.
  • the differences between the method of the present invention and the '827 method have led to significant improvements in the method, including improvements involving scale optimization, safety, yield enhancement, and purity and overall method improvements.
  • the '827 method also has the disadvantage of separation. In all steps, the reaction product is purified on a chromatographic column, which is a very expensive separation method and cannot be used on an industrial scale.
  • the method of the present invention uses centrifugation, filtration, recrystallization and other means for separation, and is more suitable for large-scale production.
  • the present invention provides a method for synthesizing compound A crystal form VI with high purity and high chiral purity, which is safe and suitable for large-scale production, and can be used in a composition containing compound A crystal form VI.
  • Compound A, Form VI is produced in a commercial-scale method.
  • commercial-scale method refers to a method that runs in a single batch of at least about 100 g.
  • the method of the present application produces compound A crystal form VI with improved yield (>90%) and limited impurities.
  • purity refers to the content of compound A crystal form VI based on HPLC. Purity is based on the "organic" purity of the compound. Purity does not include water, solvents, metals, inorganic salts, etc. By comparing the area under the peak, the purity of compound A crystal form VI was compared with the purity of the reference standard.
  • Compound A, Form VI has a purity of not less than about 96%. In another embodiment, Compound A, Form VI has a purity of not less than about 98%. In another embodiment, Compound A, Form VI has a purity of not less than about 98.5%. In another embodiment, Compound A, Form VI has a purity of not less than about 99%. In another embodiment, Compound A, Form VI has a purity of not less than about 99.5%.
  • the purity of compound A crystal form VI is 96.0%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97.0%, 97.1% , 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8 %, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
  • the compound A crystal form VI prepared by the present invention contains a chiral carbon atom and belongs to the R-configuration.
  • the chiral center of compound A crystal form VI was introduced from the starting material and did not participate in the subsequent steps, and no racemization phenomenon was found.
  • chiral purity refers to the chiral purity of compound A crystal form VI determined based on chiral high performance liquid chromatography. Chiral purity is based on the "organic" purity of the compound. Chiral purity does not include water, solvents, metals, inorganic salts, etc. By comparing the area under the peak, the chiral purity of compound A crystal form VI was compared with the chiral purity of the reference standard.
  • Compound A, Form VI has a chiral purity of not less than about 96%. In another embodiment, Compound A, Form VI has a chiral purity of not less than about 98%. In another embodiment, Compound A, Form VI has a chiral purity of not less than about 99%. In another embodiment, Compound A, Form VI has a chiral purity of not less than about 99.4%.
  • the chiral purity of compound A crystal form VI is 96.0%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97.0%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7% , 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
  • the present invention relates to Compound A crystalline Form VI containing less than about 0.8% of total impurities. In another embodiment, the total impurities are less than about 0.5%. In another embodiment, the total impurities are less than about 0.3%. In another embodiment, the total impurities are less than about 0.2%.
  • the present invention relates to compound A crystalline form VI containing no more than about 1% water, no more than about 0.8% water, no more than about 0.7% water, no more than about 0.6% water, no more than about 0.5% water, not more than about 0.4% water, not more than about 0.3% water, not more than about 0.2% water, not more than about 0.1% water, not more than about 0.09% water, not more than about 0.08% No more than about 0.07% of water, no more than about 0.06% of water, no more than about 0.05% of water.
  • the present invention relates to crystal A, Form VI containing no more than about 0.11% water.
  • the present invention relates to crystal A, Form VI containing no more than about 0.1% water.
  • the present invention relates to Crystal A, Form VI containing no more than about 0.09% water.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a pharmaceutically active ingredient: the crystalline form of the free base of Compound A or the crystalline form of a pharmaceutically acceptable salt thereof, (ii) a diluent, and (iii) Disintegrants, (iv) glidants, and (v) lubricants.
  • the active ingredient of the drug is the crystal form of compound A free base; preferably, the crystal form is selected from compound A crystal form I, compound A crystal form II, compound A crystal form III, Compound A crystal form IV, compound A crystal form V, compound A crystal form VI, compound A crystal form VII, compound A crystal form VIII, compound A crystal form IX, compound A crystal form X and compound A crystal form XI; preferably The crystal form is selected from compound A crystal form I, compound A crystal form IV, compound A crystal form VI and compound A crystal form XI.
  • the pharmaceutical active ingredient is compound A hydrochloride crystal form I, compound A besylate salt crystal form I, compound A p-toluenesulfonate salt crystal form I, compound A p-toluenesulfonic acid Salt crystal form II, compound A mesylate salt crystal form I or compound A hydrobromide salt crystal form I; preferably, the crystal form is selected from compound A besylate salt crystal form I, compound A p-toluenesulfonic acid Salt crystalline form I, compound A p-toluenesulfonate crystalline form II or compound A mesylate crystalline form I.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the pharmaceutical active ingredient to the total weight of the pharmaceutical composition is 1-30%, preferably 5-20%, preferably 8-15%, more preferably about 10%. %, calculated by the weight of the free base of the compound; preferably, the content of the active pharmaceutical ingredient in the unit dose is 1-100 mg, preferably 5-50 mg, preferably 8-40 mg, preferably about 10, 20, 30 or 40mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the diluent to the total weight of the pharmaceutical composition is 65-95%, preferably 70-90%, preferably about 80%, 81%, 82%, 83%, 84% or 85%; preferably, the content of the diluent in the unit dose is 65-380 mg, preferably 70-360 mg, preferably 80-350 mg, for example about 83 mg or 332 mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the diluent is selected from lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch, and mixtures thereof; preferably, Microcrystalline cellulose is microcrystalline cellulose 102; lactose monohydrate is selected from lactose monohydrate Granulac 200, lactose monohydrate Tablettose 80 and lactose monohydrate Preferably, when lactose monohydrate and microcrystalline cellulose are present at the same time, the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1 to 1:5, preferably 2:1 to 1:3, preferably about 1:2 , For example 1:1.96.
  • the diluent is selected from lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch, and mixtures thereof; preferably, Microcrystalline cellulose is microcrystalline cellulose 102; lactose monohydrate
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the disintegrant to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 3%; preferably, wherein The content of the disintegrant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 3, 6, 9 or 12 mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the disintegrant is croscarmellose sodium.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the glidant to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 3%; preferably, wherein ( iv) The content of glidant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 3, 6, 9 or 12 mg.
  • the present invention provides the aforementioned pharmaceutical composition, wherein the glidant is colloidal silica.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the lubricant in the total weight of the pharmaceutical composition is 0.1-5%, preferably 0.5-2%, preferably about 1%; preferably, wherein the The content of the lubricant in the unit dose is 0.1-20 mg, preferably 0.5-8 mg, preferably about 1, 2, 3 or 4 mg.
  • the present invention provides the aforementioned pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearyl fumarate.
  • the present invention provides the above-mentioned pharmaceutical composition, which comprises the following ingredients:
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the unit dose contains the following ingredients:
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the unit dose contains the following ingredients:
  • the present invention provides a pharmaceutical composition comprising:
  • the weight percentage of the glidant is 1-5% of the total weight of the pharmaceutical composition, preferably 2-4%, preferably about 3%.
  • the present invention provides the aforementioned pharmaceutical composition, wherein the glidant is colloidal silica.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the content of the glidant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 3, 6, 9 or 12 mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the diluent to the total weight of the pharmaceutical composition is 65-95%, preferably 70-90%, preferably about 80%, 81%, 82%, 83%, 84% or 85%; preferably, the content of the diluent in the unit dose is 65-380 mg, preferably 70-360 mg, preferably 80-350 mg, for example about 83 mg or 332 mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the diluent is selected from lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch, and mixtures thereof; preferably, When lactose monohydrate and microcrystalline cellulose are present at the same time, the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1 to 1:5, preferably 2:1 to 1:3, preferably about 1:2, such as 1 :1.96.
  • the diluent is selected from lactose monohydrate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch, and mixtures thereof; preferably, When lactose monohydrate and microcrystalline cellulose are present at the same time, the weight ratio of lactose monohydrate to microcrystalline cellulose is 5:1 to 1:5, preferably 2:1 to 1:3, preferably about 1:2, such as 1 :1.96.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the disintegrant to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 3%; preferably, wherein The content of the disintegrant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 3, 6, 9 or 12 mg.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the disintegrant is croscarmellose sodium.
  • the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the lubricant in the total weight of the pharmaceutical composition is 0.1-5%, preferably 0.5-2%, preferably about 1%; preferably, wherein the The content of the lubricant in the unit dose is 0.1-20 mg, preferably 0.5-8 mg, preferably about 1, 2, 3 or 4 mg.
  • the present invention provides the aforementioned pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearyl fumarate.
  • the present invention also provides a method for preparing a tablet, the method comprising a) mixing the crystal form of compound A free base or its salt, diluent, disintegrant and glidant to form a mixture; b) adding a lubricant a) In the mixture described.
  • the present invention provides a method for treating diseases or disorders caused by Bcr-Abl in a subject, including administering to the subject an effective amount of various crystal forms of Compound A free base.
  • the subject is a human subject.
  • the compound of the present invention particularly shows therapeutic efficacy for diseases or disorders that depend on the activity of Bcr-Abl1.
  • the compounds of the present invention inhibit the ATP binding site of Bcr-Abl1 (including wild-type Bcr-Abl1 and/or mutations thereof (including T315I mutation)).
  • Cancer cells use invapodia to degrade the extracellular matrix during tumor invasion and metastasis.
  • Abl kinase activity is required for the formation of Src-induced invasive pseudopodia, which regulates the different stages and functions of invasive pseudopodia assembly. Therefore, the compounds of the present invention as inhibitors of Abl have the potential to be used as a therapeutic method for the treatment of metastatic invasive cancer.
  • Inhibitors of c-Abl kinase can be used to treat brain cancer: including the most common and most aggressive malignant primary brain tumors, glioblastoma, which can be used in a subclass of patients by immunohistochemical technology The expression of c-Abl was detected. Therefore, the new c-Abl inhibitor with high brain exposure represents a solid treatment for glioblastoma and other brain cancers.
  • the compounds of the invention can be used to treat viruses.
  • viral infections can be mediated by Abl1 kinase activity, as in the case of poxviruses and Ebola viruses.
  • Imatinib and nilotinib have been shown to stop the release of Ebola virus particles from infected cells in vitro. Therefore, it can be expected that the compound of the present invention that inhibits c-Abl kinase can be used to reduce the replication ability of pathogens.
  • Parkinson's disease is the second most common chronic neurodegenerative disease, and it has the most common familial autosomal recessive form caused by mutations in the E3 ubiquitin protein ligase (parkin).
  • the latest research shows that activated c-ABL is found in the striatum of patients with sporadic Parkinson's disease.
  • Parkin is tyrosine-phosphorylated, causing loss of its ubiquitin protein ligase and cytoprotective activity, as shown by the accumulation of Parkin protein substrate.
  • the compounds or compositions of the present invention are also used to treat the following diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis , Ulcerative colitis, Crohn's disease, septic shock, proliferative disorder, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor , Thyroid cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension , Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepitheli
  • the solid samples obtained in the experiment were analyzed with D8 advance powder X-ray diffraction analyzer (Bruker).
  • the instrument is equipped with a LynxEye detector, the 2 ⁇ scanning angle ranges from 3 o to 40 o , and the scanning step size is 0.02 o .
  • the light tube voltage and light tube current were 40KV and 40mA, respectively.
  • the instrument model used for PLM analysis is ECLIPSE LV100POL polarizing microscope (Nikon, Japan).
  • the chemical structure of the solid sample was confirmed by 1 H NMR.
  • the instrument used for 1 H NMR analysis is a Bruker Advance 300 equipped with a B-ACS 120 automatic sampling system.
  • the instrument model of differential scanning calorimetry is DSC Q200 or Discovery DSC 250 (TA, USA). After the sample is accurately weighed, it is placed in the DSC pierced sample pan, and the accurate mass of the sample is recorded. The sample is heated to the final temperature (for example, 300°C or 350°C) at a temperature increase rate of 10°C/min.
  • thermogravimetric analyzer is TGA Q500 or Discovery TGA 55 (TA, USA).
  • the sample is placed in a balanced open aluminum sample pan, and the mass is automatically weighed in the TGA heating furnace.
  • the sample is heated at a rate of 10°C/min to the final temperature (e.g., 300°C or 350°C).
  • the instrument model used for dynamic moisture absorption and desorption analysis is IGA Sorp (Hidentity Isochema).
  • the sample measurement adopts the gradient mode, the humidity range of the test is 0% to 90%, and the humidity increment of each gradient is 10%.
  • Step 1 Synthesis of 6-chloro-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (compound 3).
  • Step 2 Synthesis of (R)-6-(3-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 15).
  • Step 3 (R)-6-(3-Fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of -2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (compound 16).
  • Step 4 (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound 17) Synthesis.
  • Step 1 Preparation of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrol-1-yl)nicotinamide (Compound C)
  • demineralized water (18 volumes) was added to the reactor B.
  • the temperature is controlled at 20-30°C, and the reaction liquid in the reactor A is added dropwise to the reactor B. After the addition, control the temperature and stir for at least 15 minutes.
  • centrifuge in a centrifuge rinse the sediment with demineralized water, and collect the sediment.
  • the precipitate was dried in vacuum at 55 ⁇ 5°C for at least 10 hours, and a trace of nitrogen was blown into it during drying, and KF was sampled for testing (standard: KF ⁇ 4.0%). Stop drying the material, lower the temperature to below 30°C, take a sample and send it to HPLC for testing, and then collect the material. Put the product into a double-layer LDPE bag and tie it tightly, add a desiccant of about 10% of the product weight between the second layer and the third layer of LDPE bag, weigh, paste the intermediate label, and temporarily store at room temperature.
  • Step 2-1
  • Step 2-2
  • Step 2-1 Intermediate state (R)-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(3-fluoropyrrolidin-1-yl)pyridine-3 -Base) boric acid (compound B) or its boric acid hydrolysate or the preparation of the mixture of the two
  • Step 2-2 Preparation of compound A and its crystal form VII
  • Recrystallization (1) Add absolute ethanol (7 volumes) and p-toluenesulfonic acid monohydrate (1.5 equivalents) to the reactor under the protection of nitrogen. Raise the temperature to 75 ⁇ 5°C, keep it warm and stir for at least 1 hour. Cool down to 20 ⁇ 30°C, keep warm and stir for at least 3 hours. Centrifuge, rinse with absolute ethanol, and collect the precipitate. Under the protection of nitrogen, add acetone (6 vol), demineralized water (6 vol), filter cake (1.0 equivalent) and anhydrous sodium carbonate (1.5 equivalent) to the reaction kettle in sequence, and stir at 20-30°C for at least 1 hour. Control the external temperature to 45 ⁇ 5°C, and concentrate under reduced pressure to 6-8 volumes. Cool down to 20-30°C, centrifuge, rinse with demineralized water, and collect the sediment.
  • Recrystallization (2) Under the protection of nitrogen, add absolute ethanol (10 volumes) to the reaction kettle, add filter cake and p-toluenesulfonic acid monohydrate (1.5 equivalents) under stirring, heat up to 75 ⁇ 5°C, keep warm and stir At least 1 hour. Cool down to 20 ⁇ 30°C, keep warm and stir for at least 3 hours. Centrifuge, rinse with absolute ethanol, and collect the precipitate. Under the protection of nitrogen, add acetone (6 vol), demineralized water (6 vol), filter cake (1.0 equivalent) and anhydrous sodium carbonate (1.5 equivalent) to the reaction kettle in sequence, and stir at 20-30°C for at least 1 hour. Control the external temperature to 45 ⁇ 5°C, and concentrate under reduced pressure to 6-8 volumes.
  • the acetone solution of compound A crystal form VII (1.0 equivalent dissolved in 15 volumes of acetone) passing through the microporous filter was added to the reaction kettle. Control the temperature at 50 ⁇ 80°C, steam to 7-9 volume under normal pressure; add n-heptane (7.5 volume) passing through the microporous filter element, and steam to 7-9 volume under normal pressure; add n-heptane (7.5 volume) passing through the microporous filter element Volume), steam to 7-9 volume under normal pressure, and the internal temperature rises to 75 ⁇ 5°C. Cool down to 20 ⁇ 30°C, keep warm and stir for at least 3 hours.
  • compound A is used as the starting material, and several methods such as cooling crystallization, evaporation crystallization, suspension transformation, elution crystallization, heat treatment and grinding crystallization are used to carry out the free base of compound A. Screening of polymorphs of bases.
  • a total of 11 crystal forms were found: one crystal form (Compound A crystal form VI), two hydrate crystal forms (Compound A crystal form III and Compound A crystal form VII), and eight solvate crystal forms ( Compound A crystalline form I, Compound A crystalline form II, Compound A crystalline form IV, Compound A crystalline form V, Compound A crystalline form VIII, Compound A crystalline form IX, Compound A crystalline form X, and Compound A crystalline form XI).
  • crystal form II was obtained in acetonitrile/methyl tert-butyl ether.
  • Form III is obtained in acetone/water.
  • Example 3.1 The suspension of methanol, ethanol, isopropanol, isobutanol, toluene, methyl tert-butyl ether and water of the remaining compound A crystal form I in Example 3.1 was subjected to slurrying study, and stirred at room temperature for 3 days . Solids were obtained in methanol, ethanol, isopropanol, isobutanol, water, toluene and methyl tert-butyl ether, and subjected to PLM and XRPD tests. The results showed that in addition to obtaining crystal form I and crystal form III, four new crystal forms were obtained in methanol, isobutanol, methyl tert-butyl ether and toluene.
  • crystal form I is obtained in a suspension of ethanol; crystal form III is obtained in a suspension of water; a new crystal form is obtained in a suspension of methanol, named crystal form IV, which is a methanol solvent
  • crystal form V which is an isobutanol solvate; a new crystal form is obtained in a suspension of methyl tert-butyl ether
  • crystal form VI is an anhydrous crystal form; a new crystal form is obtained in a suspension of toluene, named as crystal form VII, which is a hydrate.
  • Example 3.1 The remaining 13 single filtrates used to pave 96-well plates in Example 3.1 were placed in a fume hood and dried. No solids were obtained in water, isopropanol and isobutanol, and solids appeared in other solvents. Conducted PLM and XRPD tests. The results showed that in addition to crystal form II, crystal form III, crystal form IV and crystal form VII, a new crystal form was obtained, named VIII.
  • crystal form II is a crystal obtained by evaporation in a single solvent of acetonitrile, which is an acetonitrile solvate
  • crystal form III is a crystal obtained by evaporation in a single solvent of acetone, which is a hydrate
  • crystal form IV is a crystal obtained by evaporation in a single solvent of acetone
  • the crystal obtained by evaporation in the crystal is a methanol solvate
  • the crystal form VII is a crystal obtained by evaporation in toluene, which is a hydrate
  • a new crystal is obtained by evaporation in ethanol, named crystal form VIII, which is an ethanol solvent Compound.
  • Example 3 The various crystal forms obtained in Example 3 were characterized.
  • the compound crystal form I was prepared according to the method in Example 1, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA. The specific results are as follows:
  • Figure 1 shows the XRPD data of Compound A Form I collected according to General Method 1.
  • Table 4.1 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ ° (°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form I was subjected to PLM analysis by general method 2. It is observed that the sample is irregular flaky particles with a particle size of less than 50 ⁇ m.
  • the collected compound A crystal form I was subjected to DSC analysis by general method 4. DSC analysis showed that the peak temperature of the melting endothermic peak was 172.95°C, and the onset temperature was 170.67°C.
  • the compound A crystal form I was heated to 150° C. by DSC and the solvent was removed. The crystal form changed to form VI, as shown in Figure 3.
  • TGA analysis was performed on the collected compound A crystal form I by general method 5. TGA showed that before 200°C, the weight loss was about 5.1%, and the weight loss was mainly ethanol.
  • FIG. 2 shows the DVS spectrum of Compound A Form I collected by General Method 6.
  • DVS analysis shows that the sample is slightly hygroscopic. The water absorption is about 0.2% under 0-60%RH conditions, the water absorption under 0-80%RH conditions is about 0.7%, and the water absorption under 0-90%RH conditions is about It is 1.3%.
  • Figure 4 shows the XRPD data of Compound A Form II collected according to General Method 1.
  • Table 4.2 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form II was analyzed by PLM by general method 2. It was observed that the sample was irregularly lumpy.
  • DSC analysis was performed on the collected compound A crystal form II by general method 4. DSC analysis showed that the peak temperature of the melting endothermic peak was 115.17°C, and the onset temperature was 109.08°C.
  • TGA analysis was performed on the collected compound A crystal form II by general method 5. TGA analysis showed a weight loss of about 1.9% before 200°C.
  • the crystal form III of Compound A was obtained by suspending and crystallizing in a single water solvent, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA.
  • the specific results are as follows:
  • Figure 5 shows the XRPD data of Compound A Form III collected according to General Method 1.
  • Table 4.3 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form III was subjected to PLM analysis by general method 2. It was observed that the sample was irregularly lumpy.
  • the collected compound A crystal form III was subjected to DSC analysis by general method 4. DSC analysis showed that the peak temperature of the melting endothermic peak was 172.83°C, and the onset temperature was 171.83°C.
  • the collected compound A crystal form III was subjected to TGA analysis by general method 5. TGA analysis showed a weight loss of about 3.5% before 200°C.
  • the crystal form IV of Compound A was obtained by cooling and crystallization in methanol solution, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA. The specific results are as follows:
  • Figure 6 shows the XRPD data of Compound A Form IV collected according to General Method 1.
  • Table 4.4 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form IV was subjected to PLM analysis by general method 2. The sample was observed to be microcrystalline.
  • the collected compound A crystal form IV was subjected to DSC analysis by general method 4. DSC analysis showed that the peak temperature with the melting endothermic peak was 175.84°C, and the onset temperature was 174.03°C. In addition, at higher temperatures there is an endothermic peak with a peak temperature of 250.71°C and an onset temperature of 250.64°C.
  • TGA analysis was performed on the collected compound A crystal form IV by general method 5. TGA analysis showed a weight loss of about 3.7% before 200°C.
  • the crystal form V of compound A was obtained by suspending and crystallizing a single isobutanol solution, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA.
  • the specific results are as follows:
  • Figure 7 shows the XRPD data of Compound A Form V collected according to General Method 1.
  • Table 4.5 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form V was analyzed by PLM by general method 2. The sample was observed to be microcrystalline.
  • the collected compound A crystal form V was analyzed by DSC by general method 4. DSC analysis showed that the peak temperature of the melting endothermic peak was 173.42°C, and the onset temperature was 171.38°C.
  • TGA analysis was performed on the collected compound A crystal form V by general method 5. TGA analysis showed a weight loss of about 6.5% before 200°C.
  • Example 2 According to the industrial method in Example 2, the crystal form VI of Compound A was obtained and characterized by XRPD, PLM, NMR, MS, UV, DSC, TGA, DVS and IR. The specific results are as follows:
  • Figure 8 shows the XRPD data of Compound A Form VI collected according to General Method 1.
  • Table 4.6-1 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form VI was subjected to PLM analysis by general method 2. The sample was observed to be microcrystalline.
  • Sample analysis accurately weigh 52.15mg of compound A crystal form VI, add 0.6mL DMSO-d 6 , and after completely dissolve it, transfer to a nuclear magnet tube for 1 H-NMR, 13 C-NMR, DEPT, 19 F-NMR, HSQC, HMBC, COSY, NOESY and HF NOESY tests.
  • Figure 9 shows the proton nuclear magnetic resonance spectrum of compound A crystal form VI
  • Table 4.6-2 shows the measurement results of compound A crystal form VI proton nuclear magnetic resonance spectrum.
  • the results show that the hydrogen spectrum gives a total of 17 hydrogen signals, including 7 methylene hydrogens, 9 methine hydrogens, and 1 active hydrogen.
  • the hydrogen signal with chemical shift at ⁇ H 10.28 (s, 1H) is not related to HSQC.
  • Figure 10 shows the carbon nuclear magnetic resonance spectrum of compound A crystal form VI
  • Figure 11 shows the nuclear magnetic resonance DEPT spectrum of compound A crystal form VI
  • Table 4.6-3 shows the measurement results of compound A crystal form VI. The results show that: 13 C-NMR spectrum gives a total of 21 carbon signals. Combined with DEPT, it shows that it contains 4 methylene carbons, 9 methine carbons, and 8 carbons without hydrogen.
  • Figure 12 shows the 19 F-NMR spectrum of Compound A, Form VI, and Figure 13 shows the HF NOESY spectrum of Compound A, Form VI.
  • Table 4.6-4 shows the 19 F-NMR and 19 F-NMR of Compound A, Form VI.
  • HF NOESY spectrum test result The results show that in the HF NOESY spectrum, the chemical shift is related to H-2,6 at ⁇ -24.72, which is assigned to F 2 -7, and ⁇ -177.25 is related to H-19b, H-20, H-21, and is assigned to F -20.
  • the F and HF NOESY spectra are consistent with the structure of compound A.
  • Figure 14 shows the NMR HSQC spectrum of compound A crystal form VI
  • Figure 15 shows the nuclear magnetic resonance HMBC spectrum of compound A crystal form VI
  • Table 4.6-5 shows the HSQC and HMBC spectrum test results of compound A crystal form VI.
  • H-11 is related to C-9, C-13, C-14, C-15
  • H-14 is related to C-9, C-10, C-13
  • H-16 is related to C -12
  • C-15 is related
  • H-17 is related to C-15
  • C-18 is related
  • H-18 is related to C-12
  • C-15 is related
  • H-19a is related to C-20
  • H-19b is related to C-20
  • C-22 is related
  • H-20 is related to C-19
  • C-22 is related
  • H-21 is related to C-19
  • C-20 is related
  • H-22 is related to C-13
  • C- 21 is related, consistent with the presence of Fragment B in the structure
  • H-2,6, H-3,5 are related to C-1, C-4, combined with chemical shift and
  • Figure 16 shows the NMR COSY spectrum of compound A crystal form VI
  • Figure 17 shows the NMR NOESY spectrum of compound A crystal form VI
  • Table 4.6-6 shows the COSY and NOESY spectrum test results of compound A crystal form VI.
  • H-17 is related to H-18
  • H-20 is related to H-19a
  • H-21 is related to H-21, which further proves that there is Fragment B in the structure
  • H-2 The correlation between ,6 and H-3,5 further proves the existence of Fragment A in the structure.
  • NH-8 is related to H-3,5, suggesting that C-4 of Fragment A is connected to N-8 of Fragment B.
  • the COSY and NOESY spectrum data are consistent with the structure of compound A.
  • Figure 18 shows the mass spectrum of compound A crystal form VI.
  • the results show that the mass-nucleus ratio of the ion peak shown in the high-resolution mass spectrum is 464.1102 [M+H] + , the deviation from the theoretical value is less than 5 ppm, (theoretical value 464.1101, C 21 H 18 ClF 3 N 5 O 2 ), suggesting that the molecular formula of the sample is C 21 H 17 ClF 3 N 5 O 2 , which is consistent with the structure of compound A.
  • Sample analysis accurately weigh 24.59 mg of compound A crystal form VI sample, fully dissolve the methanol and dilute to 100 mL, and mix; take 1.0 mL of the resulting solution into a 25 mL volumetric flask, dilute to constant volume, and mix.
  • Figure 19 shows the UV spectrum of Compound A, Form VI.
  • Table 4.6-7 shows the UV measurement results of compound A crystal form VI.
  • the absorption peaks of ⁇ max 306, 263, and 201nm observed in methanol solution are the absorption peaks of the long-chain conjugated system of the compound and the ⁇ - ⁇ * transition of the substituted benzene ring, which are consistent with the structure of compound A.
  • Figure 20 shows the DSC spectrum of Compound A, Form VI collected by General Method 3.
  • DSC DSC
  • an endothermic peak of melting of the sample was observed at 174.95°C, and the starting temperature was 174.20°C, indicating that the melting point of compound A crystal form VI was 175°C.
  • the crystal form of compound A crystal form VI did not change, as shown in Fig. 3.
  • Figure 21 shows the TGA spectrum of Compound A, Form VI collected by General Method 4.
  • TGA a weight loss of 0.003174% is observed before 200°C, indicating that Type VI does not contain crystal water.
  • Figure 22 shows the DVS spectrum of Compound A, Form VI collected by General Method 6. DVS analysis shows that the water absorption under 10%RH conditions is 0.1389%, the water absorption under 0-80%RH conditions is 1.1852%, and the water absorption under 0-90%RH conditions is 1.7452%.
  • Sample analysis Weigh 303.12 mg of potassium bromide and 3.61 mg of compound A crystal form VI sample, mix them evenly, and grind into powder. Use KBr tableting method to press tablets, polystyrene film calibration, and collect the infrared spectrum of this product in the range of 4000-400cm -1 infrared spectroscopy.
  • Figure 23 shows the IR spectrum of Compound A, Form VI.
  • Table 4.6-8 shows the IR measurement results of compound A crystal form VI.
  • 3293cm- 1 is the stretching vibration absorption peak of NH, indicating that the structure contains NH structure
  • 1466, 1408cm -1 is the flexural vibration absorption peak of CH bond, indicating that the structure contains CH 2 , CH structure
  • 1210cm -1 is the stretching vibration absorption peak of COC bond, indicating that the structure contains COC structure .
  • Example 3.2 the compound A crystal form VII was obtained by suspending and crystallizing in a single toluene solvent, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA. The specific results are as follows:
  • Figure 24 shows the XRPD data of Compound A Form VII collected according to General Method 1.
  • Table 4.7 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form VII crystal form PLM was analyzed by general method 2. The sample was observed to be microcrystalline.
  • the collected compound A crystal form VII was analyzed by general method 4 by DSC. DSC analysis showed that the peak temperature of the melting endothermic peak was 173.61°C, and the onset temperature was 172.39°C.
  • TGA analysis was performed on the collected compound A crystal form VII by general method 5. TGA analysis showed a weight loss of about 3.4% before 200°C.
  • Example 3.3 the crystalline compound A crystal form VIII obtained by evaporation of a single ethanol solvent was characterized by XRPD, PLM and 1 H NMR. The specific results are as follows:
  • Figure 25 shows the XRPD data of Compound A Form VIII collected according to General Method 1.
  • Table 4.8 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form VIII was subjected to PLM analysis by general method 2. The sample was observed to be microcrystalline.
  • Figure 26 shows the XRPD data of Compound A Form IX collected according to General Method 1.
  • Table 4.9 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form IX was subjected to PLM analysis by general method 2. The sample was observed to be microcrystalline.
  • the collected compound A crystal form IX was analyzed by general method 4 by DSC. DSC analysis showed that the peak temperature of the melting endothermic peak was 173.92°C, and the onset temperature was 172.14°C.
  • TGA analysis was performed on the collected compound A crystal form IX by general method 5. TGA analysis showed a weight loss of about 5.8% before 200°C.
  • Figure 27 shows the XRPD data of Compound A Form X collected according to General Method 1.
  • Table 4.10 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form X was analyzed by general method 4 by DSC. DSC analysis showed that the peak temperature of the melting endothermic peak was about 172.54°C, and the onset temperature was 171.38°C.
  • TGA analysis was performed on the collected compound A crystal form X by general method 5. TGA analysis showed a weight loss of about 3.6% before 200°C.
  • the crystal form XI of Compound A was obtained by cooling and crystallization from an acetonitrile solution, and characterized by XRPD, PLM, 1 H NMR, DSC and TGA.
  • the specific results are as follows:
  • Figure 28 shows the XRPD data of Compound A Form XI collected according to General Method 1.
  • Table 4.11 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A crystal form XI was analyzed by DSC by general method 4. DSC analysis showed that the peak temperature of the melting endothermic peak was 174.45°C, and the onset temperature was 172.7°C.
  • TGA analysis was performed on the collected compound A crystal form XI by general method 5. TGA analysis showed a weight loss of about 3.9% before 200°C.
  • a certain amount of compound A crystal form III, crystal form VI, and crystal form VII was added to a mortar and ground at room temperature, and the solid XRPD was compared before and after the mortar.
  • the initial attempt to prepare the crystalline salt of Compound A with Compound A Crystal Form I as the starting material included two stages.
  • the first stage includes the solubility study of the starting material and the salt-forming screening in 96-well plates; the second stage is the milligram-scale scale-up preparation of the crystal salt that may be formed.
  • These initial attempts found five crystalline salt forms of Compound A, namely Compound A Hydrochloride Form I, Compound A Hydrobromide Form I, Compound A Methanesulfonate Form I, and Compound A p-toluenesulfonic acid Salt crystal form I and crystal form II, and compound A besylate salt crystal form I.
  • a certain amount of hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid and phosphoric acid were dissolved in 10 mL of methanol to prepare eight acid solutions with a concentration of 0.1M.
  • 364.3 mg of starting material was dissolved in acetone and diluted to 12 mL to prepare a starting material solution with a concentration of 30 mg/mL.
  • the eight acid solutions prepared above were added to the wells of each row, and the volume of acid added to each well was 65 ⁇ L (33 ⁇ L of sulfuric acid).
  • the solvent is completely evaporated, add 200 ⁇ L of solvent to each hole (the solvents for salt formation are methanol, ethanol, isopropanol, 2-butanone, isobutanol, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, Ethyl acetate and isopropyl acetate), sealed with a perforated parafilm, and placed in a fume hood at room temperature to evaporate dry. Select a sample from each column for 1 H NMR test to determine whether it is salt. Perform an XRPD test on the solid sample to confirm whether it is a crystalline form.
  • PhSO 3 H-S1 acetone 300 XRPD: Crystal, Form I.
  • PhSO 3 H-S2 Ethyl acetate 800 XRPD: Crystal, Form I.
  • PhSO 3 H-S3 Acetonitrile 900 XRPD: Crystal, Form I.
  • PhSO 3 H-S4 2-butanone 500 XRPD: Crystal, Form I.
  • PhSO 3 H-S5 Isopropyl acetate 2000 XRPD: Crystal, Form I.
  • Figure 31 shows the XRPD data of Compound A Hydrochloride Form I collected according to General Method 1.
  • Table 7.1 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the collected compound A hydrochloride crystalline form I prepared according to the method in Example 6.3 was subjected to PLM analysis by showing the general method 2. It was observed that the samples of the HCl-S1 and HCl-S2 batches were irregular flaky granular crystals.
  • 1 H NMR of Compound A hydrochloride Form I has a chemical shift, is determined as a salt form.
  • the collected HCl-S1 batch of compound A hydrochloride crystalline form I prepared according to the method in Example 6.3 was analyzed by general method 4 by DSC.
  • the compound A hydrochloride crystal form I sample has a melting endothermic peak with a peak temperature of 229.41°C and an onset temperature of 209.08°C.
  • the collected HCl-S1 batch of compound A hydrochloride crystalline form I was subjected to TGA analysis by general method 5.
  • the compound A hydrochloride crystalline form I sample had a weight loss of 0.6752% before 175°C.
  • Figure 32 shows the DVS spectrum of the HCl-S1 batch of compound A hydrochloride crystalline form I prepared according to the method in Example 6.3 collected by general method 6.
  • the compound A hydrochloride crystal form I sample is slightly hygroscopic, the water absorption is about 0.4% under the condition of 0-40%RH (relative humidity), and the water absorption is about 2.8 under the condition of 0-90%RH. %, as shown in Figure 32.
  • Figure 34 shows the XRPD data of Compound A benzenesulfonate crystalline form I of the PhSO 3 H-S1 batch in Example 6.4 collected according to General Method 1.
  • Table 7.2 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • DSC analysis was performed on the compound A besylate crystalline form I of the batch of PhSO 3 H-S1 collected in Example 6.4 by the general method 4.
  • the compound A besylate salt crystal form I sample has a narrow melting endothermic peak with a peak temperature of 252.81°C and an onset temperature of 252.22°C.
  • Figure 35 shows the DVS spectrum of Compound A benzenesulfonate crystalline form I of the batch of PhSO 3 H-S1 in Example 6.4 collected by General Method 6.
  • the compound A besylate salt crystal form I sample has slight hygroscopicity, the water absorption is about 0.4% under the condition of 0-60% RH, and the water absorption is about 1.5% under the condition of 0-90% RH.
  • Figure 37 shows the XRPD data of compound A p-toluenesulfonate crystalline form I of the PTAS-S1 batch in Example 6.5 collected according to general method 1.
  • Table 7.3 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • DSC analysis of the compound A p-toluenesulfonate crystalline form I of the PTSA-S1 batch collected in Example 6.5 was performed by the general method 4.
  • the compound A p-toluenesulfonate crystalline form I sample has a narrow melting endothermic peak with a peak temperature of 236.18°C and an onset temperature of 234.56°C.
  • the collected PTSA-S1 batch of compound A p-toluenesulfonate crystalline form I was subjected to TGA analysis by general method 5.
  • the compound A p-toluenesulfonate crystalline form I sample has a weight loss of 0.1415% before 200°C.
  • Figure 38 shows the DVS spectrum of PTSA-S1 batch of compound A p-toluenesulfonate crystalline form I in Example 6.5 collected by General Method 6.
  • the compound A p-toluenesulfonate crystalline form I sample has slight hygroscopicity, the water absorption is about 0.39% under the condition of 0-80% RH, and the water absorption is about 0.61% under the condition of 0-90% RH.
  • Figure 40 shows the XRPD data of compound A p-toluenesulfonate crystalline form II of the PTAS-S2 batch in Example 6.5 collected according to general method 1.
  • Table 7.4 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • DSC analysis was performed on the compound A p-toluenesulfonate crystal form II of the PTSA-S2 batch collected in Example 6.5 by the general method 4.
  • the compound A p-toluenesulfonate crystalline form II sample has a narrow melting endothermic peak with a peak temperature of 234.45°C and an onset temperature of 232.18°C.
  • TGA analysis was performed on the compound A p-toluenesulfonate crystalline form II of the PTSA-S2 batch collected in Example 6.5 by the general method 5.
  • the compound A p-toluenesulfonate crystalline form II sample has a weight loss of 0.2437% before 200°C.
  • FIG. 41 shows the XRPD data of the compound A mesylate salt crystalline form I of the CH 3 SO 3 H-S1 batch in Example 6.7 collected according to the general method 1.
  • Table 7.5 provides a list of XRPD peaks and their relative intensities at the diffraction angle of 2 ⁇ ° (°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • DSC analysis was performed on the compound A mesylate crystalline form I of the CH 3 SO 3 H-S1 batch of Example 6.7 collected by the general method 4.
  • the compound A mesylate salt crystalline form I sample has a narrow melting endothermic peak with a peak temperature of 206.37°C and an initial temperature of about 204.41°C.
  • TGA analysis was performed on the compound A mesylate crystalline form I of the CH 3 SO 3 H-S1 batch collected in Example 6.7 by General Method 5.
  • the compound A mesylate salt crystalline form I sample had a weight loss of 0.6541% before 200°C.
  • Figure 42 shows the DVS spectrum of the CH 3 SO 3 H-S1 batch of Compound A mesylate salt crystalline form I in Example 6.7 collected by General Method 6.
  • the compound A mesylate salt crystal form I sample has hygroscopicity, the water absorption is about 3.6% under the condition of 0-80% RH, and the water absorption is about 40.3% under the condition of 0-90% RH.
  • Figure 44 shows the XRPD data of compound A hydrobromide salt crystalline form I of the HBr-S1 batch in Example 6.8 collected according to general method 1.
  • Table 7.6 provides a list of XRPD peaks and their relative intensities at the diffraction angle 2 ⁇ °(°2 ⁇ ) ⁇ 0.2°2 ⁇ .
  • the DSC analysis of the compound A hydrobromide salt crystalline form I of the HBr-S1 batch in Example 6.8 was carried out by the general method 4.
  • the compound A hydrobromide salt crystal form I sample has a broad melting endothermic peak with a peak temperature of 250.54°C and an onset temperature of 240.88°C.
  • TGA analysis was performed on the compound A hydrobromide salt crystal form I of the HBr-S1 batch of Example 6.8 collected by General Method 5.
  • the compound A hydrobromide salt crystal form I sample had a weight loss of 0.6011% before 200°C.
  • FIG. 45 shows the DVS spectrum of the HBr-S1 batch of Compound A hydrobromide salt crystalline form I in Example 6.8 collected by General Method 6.
  • the sample of compound A hydrobromide salt crystal form I is slightly hygroscopic, and the water absorption is about 0.67% under the condition of 0-80% RH.
  • Compound A crystal form I was dissolved in SGF, FaSSIF and FeSSIF for 2 hours, and the crystal form changed, as shown in Figures 48, 49 and 50.
  • the p-toluenesulfonate has a higher solubility after 2 hours at a higher pH value because the p-toluenesulfonate dissociates as the pH value increases.
  • Example 10 Compound A single crystal X-ray structure and absolute stereochemistry
  • the single crystal of compound A was cultivated at room temperature by the slow volatilization method.
  • Method 1 Dissolve about 100 mg of compound A crystal form VI in acetone or methanol respectively, then add the anti-solvent n-heptane until the solution is slightly turbid, add 1-2 drops of solvent or raise the temperature until the solution is clear again, and the above solution Slowly evaporate at room temperature.
  • Method 2 Dissolve about 100 mg of compound A crystal form VI in methanol to prepare a saturated solution, and place the above solution at room temperature to evaporate slowly.
  • the single crystal is a bulk crystal with a structural formula of C 21 H 17 ClF 3 N 5 O 2 ⁇ 0.5CH 3 OH. It is a methanol solvate and belongs to the monoclinic crystal system and the C2 space group.
  • the single crystal structure is shown in Figure 54. Each unit includes two compound A molecules and one methanol molecule.
  • the host molecule has the same molecular structure as compound A.
  • the analyzed crystal structure parameters are shown in Table 10.
  • the test results of shape, crystal form and related substances showed that the compound A crystal form VI is exposed to high temperature (60°C), high humidity (25°C/92.5%RH), high temperature and high humidity (40°C/75%RH), light (visible light) It is stable for 30 days under the conditions of 4500Lux ⁇ 500Lux, near ultraviolet light 85 ⁇ w/cm2), and stable for 10 days under light conditions, and the crystal form has not undergone changes, as shown in Figure 55.
  • the inventors investigated the influence of the addition of solubilizers and glidants on the dissolution of Compound A formulations. It was found that after adding sodium lauryl sulfate as a solubilizer, the dissolution of compound A in the formulation decreased as the amount of sodium lauryl sulfate increased. However, it was found that when the glidant colloidal silica 200 is added, the elution of compound A can be improved.
  • Table 12-1 Composition of tablets used in glidant research
  • Dissolution device Chinese Pharmacopoeia 2015 edition, 0931, the second method (paddle method) Dissolution medium 0.1N HCl+0.8%SDS Medium volume 900mL Medium temperature 37 ⁇ 0.5°C Stirring paddle speed 75rpm (60-75min is the ultimate speed test, the speed is 250rpm) Sampling time point 5min, 15min, 30min, 45min, 60min, 75min
  • Example 13 Representative tablet formulation of Compound A, Form VI
  • the immediate-release film-coated tablets with doses of 10 mg and 40 mg were prepared using the powder direct compression process.
  • the composition of the tablets is provided in Table 13.
  • the 10mg and 40mg tablets of this product are equal ratio prescriptions, using the same batch of total mixed materials, and then separately compressed into tablets of different specifications. Taking the total mixed batch of 14000 tablets of 10mg and 40mg each as a representative, the batch prescription information is shown in Table 13-2.
  • the method of preparing tablets is as follows:
  • Main mixing Add mixture 1, lactose monohydrate, compound A crystal form VI, and croscarmellose sodium into a hopper for mixing in sequence at a mixing speed of 15 rpm and a mixing time of 15 minutes.
  • Total mixing add magnesium stearate to the hopper mixer for total mixing, the mixing speed is 15 rpm, and the mixing time is 5 minutes.
  • Tableting 10mg tablets have a 6mm dimple circular punch, and 40mg tablets have a 10.0mm dimple circular punch. After the equipment is debugged, the formal production is carried out. Online monitoring of tablet weight, hardness and friability to make it meet the following tabletting standards, as shown in Table 13-3:
  • Coating A 12% Opadry coating solution is freshly prepared with purified water. Set the inlet air temperature to 50-60°C and the rotating speed of the coating pan to 2rpm for preheating. When the coating pan is preheated to the exhaust temperature to 42°C, spray coating, set the inlet air temperature to 50 ⁇ 70°C, the speed of the pan is 5 ⁇ 12rpm, the inlet air volume is 300 ⁇ 100m 3 /h; 10mg tablets: pump Flow rate 8ml/min ⁇ 30ml/min, atomization pressure 0.5 ⁇ 0.3bar, atomization angle control pressure 1 ⁇ 0.5bar; 40mg tablets: pump flow 8ml/min ⁇ 40ml/min, atomization pressure 1.5 ⁇ 1bar, mist The chemical angle control pressure is 1.5 ⁇ 1bar; the coating parameters and coating weight gain are monitored, and the spraying is stopped when the coating weight gain reaches the target range of 2.5 to 3.5%. Stop heating, adjust the speed of the coating pan to 5rpm, the airflow rate is 200 ⁇ 500m 3 /h, and the material
  • Packaging The packaging materials of 10mg tablets and 40mg tablets are 45mL and 75mL oral solid medicinal high-density polyethylene bottles, respectively, with 30 tablets per bottle.

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Abstract

L'invention concerne une forme cristalline d'une base libre ou d'un sel pharmaceutiquement acceptable de (R)-N-(4-(chlorodifluorométhoxy)phényl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (composé A), son procédé de préparation, et l'utilisation du composé dans la préparation de médicaments pour le traitement de maladies médiées par Bcr-Abl-kinase et des mutants de celle-ci, telles que la leucémie myéloïde chronique. L'invention concerne également un procédé de préparation du composé A, et une préparation contenant le composé A.
PCT/CN2021/088378 2020-04-20 2021-04-20 Forme solide de nicotinamide substitué par pyrazine, sa préparation et son utilisation WO2021213380A1 (fr)

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CN202311156373.3A CN117304171A (zh) 2020-04-20 2021-04-20 吡嗪取代的烟酰胺的固体形式及其制备和用途
CN202180029222.4A CN115413277B (zh) 2020-04-20 2021-04-20 吡嗪取代的烟酰胺的固体形式及其制备和用途
US17/920,001 US20230322717A1 (en) 2020-04-20 2021-04-20 Solid form of pyrazine substituted nicotinamide, and preparation and use thereof
JP2022563455A JP2023522110A (ja) 2020-04-20 2021-04-20 ピラジン置換ニコチンアミドの固体形態ならびにその調製および使用

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104302634A (zh) * 2012-05-15 2015-01-21 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
CN104334529A (zh) * 2012-05-15 2015-02-04 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的化合物和组合物
CN104379574A (zh) * 2012-05-15 2015-02-25 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
WO2018133827A1 (fr) 2017-01-20 2018-07-26 深圳市塔吉瑞生物医药有限公司 Composé (hétéro)arylamide pour inhiber l'activité de la protéine kinase
CN109651359A (zh) * 2018-02-07 2019-04-19 深圳市塔吉瑞生物医药有限公司 取代的烟酰胺类化合物及药物组合物及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104302634A (zh) * 2012-05-15 2015-01-21 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
CN104334529A (zh) * 2012-05-15 2015-02-04 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的化合物和组合物
CN104379574A (zh) * 2012-05-15 2015-02-25 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
WO2018133827A1 (fr) 2017-01-20 2018-07-26 深圳市塔吉瑞生物医药有限公司 Composé (hétéro)arylamide pour inhiber l'activité de la protéine kinase
CN108602800A (zh) 2017-01-20 2018-09-28 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白激酶活性的(杂)芳基酰胺类化合物
CN109651359A (zh) * 2018-02-07 2019-04-19 深圳市塔吉瑞生物医药有限公司 取代的烟酰胺类化合物及药物组合物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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